Gene Ontology is known as a "gene dictionary." It is a bioinformatics initiative that collects descriptions of gene product functions. [1] Gene ontology consists of three domains: Cellular Component, Molecular Function, and Biological Process. These three domains allow for a holistic description of gene function and importance.
Cellular Component is the particular organelle or structure within the cell that contains the particular gene of interest. Some examples of cellular component are the mitochondria, Golgi apparatus, ribosomes, or a protein dimer.
Molecular Function is the action completed by the gene of interest throughout the cell at the molecular level. Some examples of possible molecular functions are catalytic, transporter, transduction or binding activities.
Biological Process is the series of events accomplished by assemblies of molecular functions. Some examples of biological processes are signal transduction or cellular physiological process.
What are the GO terms of the TCF4 Gene?
Cellular Components
Figure 1. Cell Diagram highlighting sites where TCF4 is active
The TCF4 gene is annotated as being active in the cytosol and nucleoplasm. Cytosol is the water-based fluid in which organelles, proteins, and other structures of the cell reside. [2] Cytosol is the liquid component of the cytoplasm. It serves as a site for a number of intracellular processes such as signal transduction. The nucleoplasm is a thick fluid that constitutes chromatin fibers made up of DNA. [3] Whenever division of cells occurs, chromatin fibers located inside the nucleoplasm show structural changes and form into chromosomes. It is reasonable that TCF4 is located within cytosol and nucleoplasm because it is known to translocate from cytoplasm to nuclei, especially in its processes of maintaining properties of human corneal epithelial stem cells. [4]
Molecular Function
Figure 2. Role of Transcription Factors
The molecular function of TCF4 is its role as a transcription factor/E-protein in protein dimerization. Protein dimerization is crucial to the regulation of many different types of proteins. Transcription factors are proteins which control the transcription of DNA into RNA. They contain DNA-binding domains which bind specific sequences of DNA which are called enhancers and promoters. Some transcription factors help form the transcription initiation complex while others stimulate or repress transcription of a particular gene of interest. Transcription regulation is the most common form of gene expression regulation. E-proteins bind with identical or similar proteins and then bind to a specific sequence of DNA called an E-box. [5] An E-box is a DNA response element that acts as a protein-binding site. It has been found to regulate gene expression in neurons, muscles, and other types of tissue.
Biological Process
Figure 3. Process of Cell Self-Destruction
Figure 4. Process of Cell Differentiation
TCF4 appears to be active (expressed) in various types of tissue before birth. It is involved in biological processes in the maturation of cells to carry out specific functions such as the self-destruction of cells (apoptosis) as well as cell differentiation especially in nervous cell tissue in the occurrence of PTHS. Apoptosis is the process of programmed cell death that occurs as a normal and controlled part of an organism's growth or development. [6] Cell differentiation is the process of how embryonic cells become specialized cells. TCF4 is highly expressed throughout the developing human central nervous system. [7] Lack of TCF4 expression results in reduction of neurons in the pontine nucleus, which is important for motor activity. This is due to the absence of activity of the heterodimer formed between TCF4 and MATH1, which is crucial for neuronal differentiation.
Conclusion
Gene ontology is important for understanding the fundamental role that TCF4 gene plays in Pitt-Hopkins Syndrome. Understanding its cellular component is important for determining its main functions as well as the biological processes that it affects. Identifying the key roles of TCF4, in relation to the nervous system, allowed me to make conclusions about the consequences of its mutations and also identify gaps in knowledge, which are addressed in my specific aims.
References Header: http://www.johncampbell-art.com/puzzle-project/ [1] Gene Ontology. (n.d.). An Introduction to the Gene Ontology. <ftp://ftp.geneontology.org/go/www/GO.doc.shtml> [2] Pure Sciences. (2017, December). What Is Cytosol? How Is It Different From Cytoplasm? <https://www.scienceabc.com/pure-sciences/what-is-cytosol-how-is-it-different-from-cytoplasm.html> [3] Innovateus. (n.d.). What is Nucleoplasm in a cell ? Retrieved from http://www.innovateus.net/health/what-nucleoplasm-cell#What are the functions of nucleoplasm%3F [4] Lu, R., Yangluowa, Q., Ge, J., Zhang, L., Su, Z., Pflugfelder, S. C., & Li, D.-Q. (2012). Transcription Factor TCF4 Maintains the Properties of Human Corneal Epithelial Stem Cells. Stem Cells (Dayton, Ohio), 30(4), 753–761. http://doi.org/10.1002/stem.1032 [5] TCF4 gene - Genetics Home Reference. (n.d.). <https://ghr.nlm.nih.gov/gene/TCF4> [6] Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Programmed Cell Death (Apoptosis) <https://www.ncbi.nlm.nih.gov/books/NBK26873/> [7] Rosenfeld, J. A., Leppig, K., Ballif, B. C., Thiese, H., Erdie-Lalena, C., Bawle, E., . . . Shaffer, L. G. (2009). Genotype–phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations. Genetics in Medicine,11(11), 797-805. doi:10.1097/gim.0b013e3181bd38a9